Our Central Theme of this Program Project revised application continues to be to accelerate our efforts to translate the biology of the endogenous particulate guanylyl cyclase (GC) activators, the natriuretic peptides (NPs), into novel therapeutics for human cardiorenal disease highly relevant to heart failure and hypertension. This is motivated by the biology, therapeutics and diagnostics of the NPs and their GC receptors linked to 3',5'cyclic guanosine monophosphate (cGMP). Indeed, studies at the molecular or cell level, in murine or large animal models, in pharmacologic or physiologic studies in normal or humans with cardiovascular or renal disease and in recent human of NP gene variants have provided a view of a humoral system with broad beneficial pleiotropic actions. These beneficial properties of NP/GC/cGMP signaling include natriuresis, vasodilatation, positive lusitropism, inhibition of myocyte apoptosis and hypertrophy, inhibition of fibroblast proliferation and collagen synthesis, suppression of aldosterone and induction of vascular regeneration. Indeed, these cGMP-mediated properties of GC receptor activation linked to the NPs represent an unprecedented opportunity for novel drug discovery. Highlights of each Project are as follows: Project 1: Enhance cardiomyocyte function through chronic overexpression of the GC-A receptor utilizing a novel gene delivery strategy in experimental diastolic heart failure (Margaret Redfield MD - Project Leader);Project 2: Advance the development of oral delivery in humans of the designer NP CD-NP and the development of a second novel GC-A/-B activator individualized for cardiorenal disease (John C Burnett Jr., MD - Project Leader);Project 3: Establish in humans with systolic and diastolic preclinical heart failure with impaired renal function the synergistic action of optimizing the NP/PDEV/cGMP pathway with chronic PDEV inhibition with chronic novel GC-A activation (Dr. Horng Chen MD - Project Leader). Thus, this application brings together a highly collaborative team of physician-scientists with a highly translational proposal which should lead to innovative therapeutics for cardiorenal disease.